Maintaining healthy cognitive functions, of which memory is a most important one, is one of the major goals of mental health research. Aging, diseases, stress and injury can lead to cognitive and memory impairments. It is estimated that up to one third of adults will experience a gradual decline in cognitive function known as mild cognitive impairment as they age. Furthermore, risk for Alzheimer<s disease, memory loss and dementia increases with increasing age. Thus, minimizing or preventing cognitive and memory loss is very important as the average life span continues to lengthen. It is therefore imperative to understand the physiology of memory formation, persistence and storage and identify molecular mechanisms and targets that are associated with memory impairments in order to develop strategies that will prevent or reverse them. Newly learned information is in a labile state for a limited time and becomes a long-term memory through a process of stabilization that is known as memory consolidation. Once stable, memory can become labile again if retrieved and re-stabilizes through another process known as memory reconsolidation. Using contextual fear conditioning types of memory in rats, we have recently found that the growth factor insulin like growth factor II (IGF-II) acts as a potent memory enhancer when administered during the consolidation or reconsolidation phases. Furthermore, using inhibitory avoidance (IA), we have found that retrieval-dependent reconsolidation promotes memory strengthening and prevents forgetting. These findings suggest that it is possible to identify post-retrieval mechanisms that can be used as targets to develop new therapies that promote cognition and alleviate age- related memory decline. Using IA and social transmission of food preference in rats, this proposal will test the molecular mechanisms and brain circuitry of the retrieval-dependent IGF-II-induced memory enhancement. It will investigate circuitry and molecular mechanisms of retrieval-induced memory strengthening and prevention of forgetting. Finally, it will investigate how memory retrieval and IGF-II can be used in aging to delay or reverse memory impairments. Results from these studies will advance our knowledge of neural mechanisms underlying memory enhancement and aging-related cognitive impairment in rats. PUBLIC HEALTH RELEVANCE: Capitalizing on recent findings from our ongoing project using the rat as an animal model, this project continuation aims at identifying the mechanisms and circuitry of memory enhancement in adult animals and in preventing or rescuing memory decay. The results of these studies may lead to the identification of new therapies that prevent or reverse memory impairments. Preventing or rescuing cognitive and memory loss is a most important goal in mental health research.